Technical Field
The field of the present invention relates to the transcobalamin receptor, particularly anti-transcobalamin receptor antibodies and the use of the antibodies in the prevention, diagnosis, and treatment of tumors, cancer and proliferative diseases and disorders.
Description of the Related Art
Cellular uptake of vitamin B12 (cobalamin, Cbl) is mediated by two proteins, transcobalamin (TC), a plasma protein secreted by the vascular endothelial cells (Quadros et al. Am J Physiol, 277, G161-6, 1999) that binds and transports the vitamin to tissues, and the membrane receptor for TC-Cbl (TCblR/CD320), which is expressed on most cell types and binds TC saturated with cobalamin to internalize the vitamin by endocytosis (Cooper and Paranchych. Nature, 191, 393-5, 1961). The TC is degraded in the lysosome, and the Cbl is transported out of the lysosome (Youngdahl-Turner et al. Exp Cell Res, 118, 127-34, 1979) for conversion to methylCbl and adenosylCbl (Quadros and Jacobsen. Biochim Biophys Acta, 1244, 395-403, 1995). The two forms of Cbl serve as cofactors for two key enzymes, methionine synthase (MS) and methylmalonylCoA mutase (MMU). The conversion of methyltetrahydrofolate and homocysteine to tetrahydrofolate and methionine by MS requires methylCbl (Taylor and Hanna. Arch Biochem Biophys, 171, 507-20, 1975), and adenosylCbl is a cofactor for MMU for the formation of succinylCoA in the propionate metabolic pathway (Hall, J Lab Clin Med, 103, 70-81, 1984). TCblR expression is coupled to the cell cycle with highest receptor expression in actively dividing cells, likely preceding DNA synthesis (Hall, J Lab Clin Med, 103, 70-81, 1984). Cellular uptake and disposition of Cbl is a dynamic process dictated by available extracellular TC-Cbl and intracellular Cbl requirement, with most of the Cbl exiting the cell following conversion to coenzyme forms and utilization in Cbl dependent reactions (Quadros and Jacobsen. Biochim Biophys Acta, 1244, 395-403, 1995). TCblR (CD320) is a membrane receptor with structural homology to the LDL receptor family. The mature protein of 282 amino acids has a 198 amino acid (aa) extracellular region (amino acids 32-229 of SEQ ID NO:53), a 21 aa transmembrane stretch and a 32 aa cytoplasmic domain. The extracellular region contains two LDL receptor type A domains separated by a 55 aa cysteine rich CUB like domain (Quadros et al. Blood, 113: 186-192, 2009). The two LDLR-A domains with consensus aa sequences for Ca++ binding appear to be critical determinants for Ca++ dependent binding of TC-Cbl (DiGirolamo and Huennekens. Arch Biochem Biophys, 168, 386-93, 1975).
Cbl plays an essential role in folate recycling, and the differential expression of the receptor serves to provide optimum delivery of the vitamin to cells during the early phase of DNA synthesis. This process ensures adequate functioning of Cbl dependent enzymes, especially the methionine synthase that is essential for recycling of methyl folate to generate folates needed for purine and pyrimidine biosynthesis (Wickramasinghe S N. Baillieres Clin Haematol 1995; 8:441-59). The more proliferative a cell, the higher the need for folates and Cbl, and this need for Cbl is met by the increased expression of TCblR in cancer cells that may have inherently lost the ability to stop dividing and differentiate. Selective targeting of cancer cells for destruction by delivering drugs and toxins preferentially to these cells has been the ultimate objective of cancer therapy.
The search for tumor specific markers and the strategies to utilize these in cancer therapy have been pursued for decades with mixed results. This can be attributed to multiple factors that include the lack of specificity of the target antigen, cellular events that can alter the targeting and to the complex and diverse nature of cancer itself.
Clearly, there is a need in the art for new agents and methods for treating tumors, e.g., by blocking cell growth or proliferation or by delivering cytotoxic and growth inhibiting agents to tumor cells.